Long noncoding RNA SNHG8 accelerates acute gouty arthritis development by upregulating AP3D1 in mice.

Gout can affect the quality of life of patients due to monosodium urate monohydrate (MSU) crystals. Numerous studies have proposed that long noncoding RNAs (lncRNAs) regulate gout. We aimed to reveal the function of lncRNA small nucleolar RNA host gene 8 (SNHG8) in acute gouty arthritis (GA). A GA mouse model was established by injection of MSU into footpads. The levels of SNHG8, miR-542-3p and adaptor-related protein complex 3 subunit delta 1 (AP3D1) in footpads were detected via polymerase chain reaction analysis. Hematoxylin-eosin staining revealed the paw swelling in mice. Enzyme-linked immunosorbent assay and western blot analysis were applied to determine the concentrations of proinflammatory cytokines. SNHG8 expression was identified to be upregulated after MSU treatment. Ablation of SNHG8 decreased the MSU-induced enhancement of paw swelling and foot thickness. In addition, SNHG8 depletion decreased the protein levels of proinflammatory factors in GA mice. Mechanically, SNHG8 was verified to be a sponge of miR-542-3p, and miR-542-3p targeted AP3D1 3' untranslated region. SNHG8 competitively bound with miR-542-3p to upregulate AP3D1 expression. Finally, results of rescue assays illustrated that AP3D1 upregulation offset the SNHG8-mediated inhibition on paw swelling and protein levels of proinflammatory factors in GA mice. In conclusion, SNHG8 accelerates acute GA development by upregulating AP3D1 in an miR-542-3p-dependent way in mice, providing an effective therapeutic approach to treat acute GA.

Apolipoprotein E ablation decreases synaptic vesicular zinc in the brain.

Both apolipoprotein E (apoE) and zinc are involved in amyloid ß (Aß) aggregation and deposition, in the hallmark neuropathology of Alzheimer's disease (AD). Recent studies have suggested that interaction of apoE with metal ions may accelerate amyloidogenesis in the brain. Here we examined the impact of apoE deficiency on the histochemically reactive zinc pool in the brains of apoE knockout mice. While there was no change in total contents of metals (zinc, copper, and iron), the level of histochemically reactive zinc (principally synaptic zinc) was significantly reduced in the apoE-deficient brain compared to wild-type. This reduction was accompanied by reduced expressions of the presynaptic zinc transporter, ZnT3, as well as of the δ-subunit of the adaptor protein complex-3 (AP3δ), which is responsible for post-translational stability and activity of ZnT3. In addition, the level of histochemically reactive zinc was also decreased in the cerebrovascular micro-vessels of apoE-deficient mice, the site of cerebral amyloid angiopathy in AD. These results suggest that apoE may affect the cerebral free zinc pool that contributes to AD pathology.

Paradoxical homozygous expression from heterozygotes and heterozygous expression from homozygotes as a consequence of transcriptional infidelity through a polyadenine tract in the AP3B1 gene responsible for canine cyclic neutropenia.

Canine cyclic neutropenia is an autosomal recessive disease in which the number of neutrophils, the primary blood phagocyte, oscillates between almost zero and normal values with two week frequency. We previously found that the causative mutation is an insertion of an extra adenine residue within a tract of nine A's in exon 21 of the 27 exon canine AP3B1 gene. In the course of identifying the mutation, however, we observed an unusual phenomenon: heterozygous carrier dogs, who have one normal allele and one mutant allele, produce a homogeneous population of normal AP3B1 transcripts (containing nine A's), but homozygous affected dogs, who have two mutant alleles, produce a heterogeneous population of AP3B1 mRNA containing mutant transcripts with ten A's and, unexpectedly, wild-type transcripts with nine A's. By RT-PCR subclone analysis and use of an in vitro reporter assay, we show that there is a high frequency of errors made during the transcription of homopolymeric adenine sequences, such that the A tract in the mRNA is frequently shortened or lengthened by an extra residue. Out of frame transcripts are degraded, accounting for this paradox through the preferential accumulation of normal message from mutant alleles.